Molecular dynamics simulations and in silico peptide ligand screening of the Elk-1 ETS domain

Hussain, A. and Shaw, P.E. and Hirst, J.D. (2011) Molecular dynamics simulations and in silico peptide ligand screening of the Elk-1 ETS domain. Journal of Cheminformatics, 3 (49). ISSN 1758-2946

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Background: The Elk-1 transcription factor is a member of a group of proteins called ternary complex factors, which serve as a paradigm for gene regulation in response to extracellular signals. Its deregulation has been linked

to multiple human diseases including the development of tumours. The work herein aims to inform the design of

potential peptidomimetic compounds that can inhibit the formation of the Elk-1 dimer, which is key to Elk-1

stability. We have conducted molecular dynamics simulations of the Elk-1 ETS domain followed by virtual screening.

Results: We show the ETS dimerisation site undergoes conformational reorganisation at the a1b1 loop. Through

exhaustive screening of di- and tri-peptide libraries against a collection of ETS domain conformations representing the dynamics of the loop, we identified a series of potential binders for the Elk-1 dimer interface. The di-peptides showed no particular preference toward the binding site; however, the tri-peptides made specific interactions with residues: Glu17, Gln18 and Arg49 that are pivotal to the dimer interface.

Conclusions: We have shown molecular dynamics simulations can be combined with virtual peptide screening to obtain an exhaustive docking protocol that incorporates dynamic fluctuations in a receptor. Based on our findings, we suggest experimental binding studies to be performed on the 12 SILE ranked tri-peptides as possible compounds for the design of inhibitors of Elk-1 dimerisation. It would also be reasonable to consider the score ranked tri-peptides as a comparative test to establish whether peptide size is a determinant factor of binding to the ETS domain.

Item Type: Article
Schools/Departments: University of Nottingham UK Campus > Faculty of Science > School of Chemistry
Identification Number:
Depositing User: Hirst, Professor Jonathan D
Date Deposited: 13 Mar 2013 14:44
Last Modified: 13 Sep 2016 20:51

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